Immature fat cells generate heat without gathering fat

Brown fat - Two FGF proteins provide similar effects on production of UCP1 but are driven by different exposures in mice - FGF9 is stimulated by cold, while FGF6 is stimulated by exercise

Researchers at Joslin Diabetes Center have discovered an unexpected biological pathway by which brown fat cells can translate energy into heat - immature fat cells can generate heat without gathering fat may open opportunities to treat obesity and diabetes.

The research team, led by Dr Yu-Hua Tseng, a Senior Investigator in the Section on Integrative Physiology and Metabolism at Joslin, have previously reported that certain biological signals that boost the production of brown fat cells are also likely to create unhelpful white fat cells, thus posing one of research challenges in enhancing brown fat activity. The finding, however, suggests that the pathway the Joslin team uncovered might offer a solution to that challenge.

In this study, ‘FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis’, published in Nature Communications, they began by examining a protein called uncoupling protein-1 (UCP1) that is located on mitochondria, the cell's powerhouses. UCP1 is known to be a crucial component in activating brown fat cells, explains Tseng, who is also an Associate Professor of Medicine at Harvard Medical School.

Her team screened more than 5,000 mammalian proteins to identify factors that heightened UCP1 production in brown fat precursor cells. The screen identified two proteins called fibroblast growth factors 6 (FGF6) and FGF9, a range of proteins that can help to regulate diverse biological processes including cell development and growth.

Next, the investigators tried increasing the levels of the two proteins, increasing UCP1 production, in immature mouse brown fat cells. The scientists expected that these cells would start to accumulate fats and other lipids, and to develop into mature brown fat cells, but surprisingly, that did not happen. Painstakingly uncovering the reasons for this resulted in an unexpected outcome.

“We found step-by-step the molecular events that happened downstream that eventually lead to UCP1 production in fat cells," explained Dr Farnaz Shamsi, a postdoctoral associate in the Tseng lab and lead author on a paper describing the findings in Nature Communications. "This novel downstream pathway was completely different from what researchers in our field have understood as the mechanism to induce UCP1 in these cells."

Shamsi, Tseng and their colleagues saw that the two FGF proteins provide similar effects on production of UCP1 but are driven by different exposures in mice. FGF9 is stimulated by cold, while FGF6 is stimulated by exercise.

When the Joslin scientists went on to analyse samples of human fat tissues, they also recognised this pathway at work. Among their results, levels of FGF9 and FGFR3 (the receptor protein that FGF9 and FGF6 both activate) were associated with higher levels of UCP1 in human brown and white fat. More strikingly, expression of FGFR3 in human white fat negatively correlated with the person's body mass index (a measure of obesity) and insulin resistance (a condition that can drive type 2 diabetes).

"This suggests that if we can activate this pathway, we potentially can benefit people with obesity, diabetes and related metabolic diseases," added Tseng.

Her team is working with collaborators to synthesize a version of the FGF protein that is optimized for greater efficacy and easier delivery, she says. Since her group has traced the mechanisms at work in this pathway, it also may eventually be possible to develop drugs that build up UCP1 production by targeting specific molecular steps in the pathway.

"As obesity becomes an epidemic, we hope that our research in brown fat can help," she added. "With a collective effort from many labs around the globe, we are getting closer to that goal."